Common side effects include nausea and vomiting when taken by mouth.[1] The skin may occasionally become red and itchy with either form.[1] A non-immune type of anaphylaxis may also occur.[1] It appears to be safe in pregnancy.[1] For paracetamol overdose, it works by increasing the level of glutathione, an antioxidant that can neutralise the toxic breakdown products of paracetamol.[1] When inhaled, it acts as a mucolytic by decreasing the thickness of mucus.[8]

Contents

Intravenous and oral formulations of acetylcysteine are available for the treatment of paracetamol (acetaminophen) overdose.[12] When paracetamol is taken in large quantities, a minor metabolite called N-acetyl-p-benzoquinone imine (NAPQI) accumulates within the body. It is normally conjugated by glutathione, but when taken in excess, the body's glutathione reserves are not sufficient to inactivate the toxic NAPQI. This metabolite is then free to react with key hepatic enzymes, thereby damaging liver cells. This may lead to severe liver damage and even death by acute liver failure.

In the treatment of acetaminophen overdose, acetylcysteine acts to maintain or replenish depleted glutathione reserves in the liver and enhance non-toxic metabolism of acetaminophen.[13] These actions serve to protect liver cells from NAPQI toxicity. It is most effective in preventing or lessening hepatic injury when administered within 8–10 hours after overdose.[13] Research suggests that the rate of liver toxicity is approximately 3% when acetylcysteine is administered within 10 hours of overdose.[12]

Although both IV and oral acetylcysteine are equally effective for this indication, oral administration is poorly tolerated because high oral doses are required due to low oral bioavailability,[14] because of its very unpleasant taste and odour, and because of adverse effects, particularly nausea and vomiting. Prior pharmacokinetic studies of acetylcysteine did not consider acetylation as a reason for the low bioavailability of acetylcysteine.[15] Oral acetylcysteine is identical in bioavailability to cysteine precursors.[15] However, 3% to 6% of people given intravenous acetylcysteine show a severe, anaphylaxis-like allergic reaction, which may include extreme breathing difficulty (due to bronchospasm), a decrease in blood pressure, rash, angioedema, and sometimes also nausea and vomiting.[16] Repeated doses of intravenous acetylcysteine will cause these allergic reactions to progressively worsen in these people.

Several studies have found this anaphylaxis-like reaction to occur more often in people given IV acetylcysteine despite serum levels of paracetamol not high enough to be considered toxic.[17][18][19][20]

Inhaled acetylcysteine has been used for mucolytic ("mucus-dissolving") therapy in addition to other therapies in respiratory conditions with excessive and/or thick mucus production. It is also used post-operatively, as a diagnostic aid, and in tracheotomy care. It may be considered ineffective in cystic fibrosis.[21] A 2013 Cochrane review in cystic fibrosis found no evidence of benefit.[22]

Some reviews found that prior administration of acetylcysteine decreases radiocontrast induced kidney disease,[23][24] whereas another found questionable effects.[25]

Despite the conflicting research outcomes, the 2012 Kidney Disease: Improving Global Outcomes Guidelines suggest the use of oral acetylcysteine for the prevention of contrast-induced nephropathy in high-risk individuals, given its potential for benefit, low likelihood of adverse effects, and low cost.[26]

Acetylcysteine has been used for cyclophosphamide-induced haemorrhagic cystitis, although mesna is generally preferred due to the ability of acetylcysteine to diminish the effectiveness of cyclophosphamide.[27][28]

Acetylcysteine can be used in Petroff's method i.e. liquefaction and decontamination of sputum, in preparation for recovery of mycobacterium.[41] It also displays significant antiviral activity against the influenza A viruses.[42]

The most commonly reported adverse effects for IV formulations of acetylcysteine are rash, urticaria, and itchiness.[13] Up to 18% of patients have been reported to experience anaphylaxis reaction, which are defined as rash, hypotension, wheezing, and/or shortness of breath. Lower rates of anaphylactoid reactions have been reported with slower rates of infusion.

Adverse effects for inhalational formulations of acetylcysteine include nausea, vomiting, stomatitis, fever, rhinorrhea, drowsiness, clamminess, chest tightness, and bronchoconstriction. Although infrequent, bronchospasm has been reported to occur unpredictably in some patients.[45]

Adverse effects for oral formulations of acetylcysteine have been reported to include nausea, vomiting, rash, and fever.[45]

The implications of these findings for long-term treatment with acetylcysteine have not yet been investigated. The dose used by Palmer and colleagues was dramatically higher than that used in humans, the equivalent of about 20 grams per day.[46][47] Nonetheless, positive effects on age-diminished control of respiration (the hypoxic ventilatory response) have been observed previously in human subjects at more moderate doses.[48]

Although N-acetylcysteine prevented liver damage when taken before alcohol, when taken four hours after alcohol it made liver damage worse in a dose-dependent fashion.[49]

Tablets - sometimes in a sustained release formula sold as a nutritional supplement

Capsules

The IV injection and inhalation preparations are, in general, prescription only, whereas the oral solution and the effervescent tablets are available over the counter in many countries. Acetylcysteine is available as a health supplement in the United States, typically in capsule form.

While many antioxidants have been researched to treat a large number of diseases by reducing the negative effect of oxidative stress, acetylcysteine is one of the few that has yielded promising results, and is currently already approved for the treatment of paracetamol overdose.[59]

It is being studied in conditions, such as autism, where cysteine and related sulfur amino acids may be depleted due to multifactorial dysfunction of methylation pathways involved in methionine catabolism.[60]

Acetylcysteine in a double-blind placebo-controlled trial appears to reduce the effects of blast induced mild traumatic brain and neurological injury in soldiers.[61] Animal studies have also demonstrated its efficacy in reducing the damage associated with moderate traumatic brain or spinal injury, and also ischaemia-induced brain injury. In particular, it has been demonstrated to reduce neuronal losses and to improve cognitive and neurological outcomes associated with these traumatic events.[34]

It has been suggested that acetylcysteine may help people with Samter's triad by increasing levels of glutathione allowing faster breakdown of salicylates, although there is no evidence that it is of benefit.[62]

It has been shown effective in the treatment of Unverricht-Lundborg disease in an open trial in four patients. A marked decrease in myoclonus and some normalization of somatosensory evoked potentials with acetylcysteine treatment has been documented.[66][67]

The effect of acetylcysteine in combination with glucocorticoids (combination group) for people who have severe alcoholic hepatitis was examined and showed that the combination of acetylcysteine with prednisolone decreased mortality significantly at one month compared to the prednisolone-only group (8% vs 24%, P=0.006). However, the improvement was not as significant at 3 months or 6 months (22% vs 34%, P=0.06) and (27% vs 38%, P=0.07). Factors that were associated with increased 6-month survival included younger age, shorter prothrombin time, lower levels of bilirubin in baseline studies, and decrease in bilirubin on day 14, all (P<0.001). Death due to hepatorenal syndrome occurred less frequently for the combination group at 6 months (9% vs 22%, P=0.02) and infections were also less frequent in the combination group as well (P=0.001). Six-month survival, the primary outcome, was not improved in conclusion.[68]

Addiction to certain addictive drugs (e.g., cocaine, heroin, alcohol, and nicotine) is correlated with a persistent reduction in the expression of excitatory amino acid transporter 2 (EAAT2) in the nucleus accumbens (NAcc);[40] the reduced expression of EAAT2 in this region is implicated in addictive drug-seeking behavior.[40] In particular, the long-term dysregulation of glutamate neurotransmission in the NAcc of addicts is associated with an increase in vulnerability to relapse after re-exposure to the addictive drug or its associated drug cues.[40] Drugs that help to normalize the expression of EAAT2 in this region, such as N-acetylcysteine, have been proposed as an adjunct therapy for the treatment of addiction to cocaine, nicotine, alcohol, and other drugs.[40]